Project Summary The prevalence of obesity, Type II diabetes, and metabolic syndrome has been attributed, in part, to nutritional, psychological, and lifestyle changes in the developed world over the past century. However, other factors may contribute to this epidemic and include influences of endocrine disrupting compounds (EDCs). One such group of EDCs is flame-retardants used in household products, furniture, clothing, toys, and electronics. These EDCs are a potential ?obesogens?, which may lead to an increase or susceptibility to obesity, metabolic syndrome, and Type II diabetes in children and adults. Organophosphate flame-retardants (OPFR) are increasing in usage due to the phase-out of PBDE flame-retardants. Three of the most common OPFR are triphenyl phosphate, tricresyl phosphate, and tris(1,3-dichloro-2-propyl) phosphate. Little is known about the effects of these compounds, at environmentally relevant concentrations, on adult energy or glucose homeostasis in humans or in rodent models. Therefore, the proposed research will be focused on the effects of adult exposure to these OPFRs, in a mixture and alone, on energy and glucose homeostasis in mice. The mechanisms behind these effects are unknown but potentially involve transcriptional effects in the hypothalamus mediated by the actions of the classical estrogen receptors (ER?) and nuclear receptors (PPAR?). Our hypothesis is that OPFR impinge on the activity of nuclear receptors, both steroid and metabolic, to exert their multi-focal effects on energy and glucose homeostasis in the hypothalamus. By investigating the effects of OPFRs on energy and glucose homeostasis, we can begin to understand the impacts of these environmental contaminants on human health. Experiments will compare the effects of OPFR in the hypothalamus using a combined approach of whole-animal physiology and behavior, gene and protein expression, electrophysiology, and peptide hormone analysis in transgenic mouse strains. In Aim 1, we will examine the effects of adult OPFR exposure on energy intake, energy expenditure, and glucose homeostasis in adults and on hypothalamic gene and protein expression via steroid and nuclear receptors. In Aim 2, we will examine the effects of adult OPFR exposure on NPY neuronal sensitivity to peripheral peptide hormones (leptin, insulin, ghrelin) and K+ channel activity and subunit expression using state-of-the-art electrophysiology coupled with single cell-type qPCR.